a. Field of the Invention:
This invention relates to a preparation process of dl-lactic acid-glycolic acid-copolymers used as matrices of molded slow-releasing drugs.
b. Description of the Prior Art:
Polylactic acid, polyglycolic acid and other similar compounds are bioabsorbable and hydrolyzable polymers. By applying these properties, these polymers are used for medical care as sutures or matrices of molded slow-releasing drugs in the form of pellet, film and bar which are administered by such methods as, for example, implanatation.
Particularly polylactic acid has better processing ability and solubility in solvents as compared with polyglycolic acid, and is frequencly used as a matrix in the form of various molded drugs. Polylactic acid, however, has a slow rate of decomposition in vivo, and is hence disadvantageous in that polylactic acid remains in the organism as long as one to several months after releasing the drugs.
Therefore, it has also been known recently to use copolymers obtained by copolymerizing lactic acid with glycolic acid.
According to the information of the present inventors in particular, a copolymer containing 50-60 mol % of a lactic acid unit and 40-50 mol % of a glycolic acid unit and also having such physical properties as a weight average molecular weight of 30,000-100,000, good solubility in chloroform and an inherent viscosity of 0.4-0.6 in a 1 g/100 ml solution has suitable absorbability in vivo and solubility. Therefore, it has already been known that the copolymer can be applied for various matrices of drugs in a wide field of medication forms and is particularly suitable for the slow-releasing drugs used for the implantation in the form such as pellet, film and micro capsule.
A low molecular weight lactic acid-glycolic acid-copolymer having a relatively high content of the lactic acid unit like the copolymer of this invention and the process for preparing the same have been disclosed in Japanese Laid-Open Patent Nos. 64824/1987 and 46823/1981.
Japanese Laid-Open Patent No. 64824/1987 discloses a low molecular weight and heterogeneous lactic acid-glycolic acid-copolymer containing 25-100 mol % of the lactic acid unit and 0-75 mol % of the glycolic acid unit, being soluble in benzene and having an intrinsic viscosity of not more than 0.5 in a 1 g/100 ml solution of benzene. It also discloses a similar copolymer containing the same proportion of the above units, being insoluble in benzene and having an intrinsic viscosity of not more than 4 in a 1 g/100 ml solution of chloroform or dioxane.
As an illustrative example of the preparation process, the above patent describes that the desired copolymer is obtained by copolymerizing a lactide with a glycolide at 160.degree. C. in the presence of dl-lactic acid containing water as a polymerization regulator by the use of stannous octoate as a catalyst in an amount of 0.2 wt. % based on the sum of the lactide and the glycolide.
In addition, Japanese Laid-Open Patent No. 46823/1981 discloses a lactic acid/glycolic acid-copolymer used for a matrix of molded slow-releasing drugs containing parasitic ascaricide and the process for preparing the same.
This patent describes that a lactic acid-glycolic acid-copolymer being derived from about 70-80 wt. % of lactic acid and about 30-20 wt. % of glycolic acid and having such desired properties as an inherent viscosity of about 0.13-0.23 in a chloroform solution and a weight average molecular weight of about 15,000-30,000 is obtained by conducting the copolymerization in the presence of a strongly acidic ion exchange resin.
As stated above in Japanese Laid-Open Patent No. 64824/1987, the copolymer having the desired properties is obtained by using stannous octoate in an amount of about 0.2 wt. % based on the sum of lactic acid and glycolic acid. However, the tin content in the molded drugs administered in vivo must, of course, be minimized.
On the other hand, it is difficult to remove tin metal from the copolymer obtained. Although stannous octoate is known to have a remarkable effect as the catalyst, stannous octoate contains a metallic tin ingredient of 28-30 wt. %. Therefore, the amount used as described in the patent inevitably causes residue of tin metal in an amount of several hundred ppm and is expected to have adverse effects to some extent.
As a result, the above Japanese Laid-Open Patent No. 46823/1981 is though to have carried out the copolymerization of lactic acid with glycolic acid by using the strongly acidic ion exchange resin in the absolute absence of the metallic catalyst.
Besides the slow-releasing drugs, no endotoxin must be contained in materials administered in vivo.
Endotoxin is lipopolysaccharides existing in cell walls of the bacteria and known to exert biological activities such as decrement in leucocytes and blood platelets, fever, hemorrhagic necrosis of bone marrow and reduction in flood sugar value.
The above Japanese Laid-Open Patent No. 64824/1987 illustrates an example for conducting the copolymerization at 160.degree. C. Polymerization at such a temperature causes a problem in the resultant polymer which enhances the possibility of containing residual endotoxin derived from monomers and other raw materials.